Intracellular Aβ42 Sequestration by a Serine Protease Mitigates Neurotoxicity in a Drosophila Alzheimer's Disease Model

ABSTRACT Emerging evidence suggests that intraneuronal Aβ accumulation represents an early pathogenic event in Alzheimer's disease (AD), preceding extracellular plaque formation and neuroinflammatory responses. However, whether targeting intracellular Aβ can halt disease progression and how this can be achieved in vivo remain unknown. While investigating the brain transcriptional responses to Aβ pathology, we identify a neuroprotective role for the serine protease Yip7 in a Drosophila AD model. Neuronal overexpression of yip7 alleviates multiple Aβ42‐induced deficits, including declines in locomotor activity, impaired proteostasis, increased brain aging and neuronal death, and shortened lifespan. Unlike canonical digestive proteases, Yip7 is not secreted but instead localized to the endosomal/lysosomal compartments via a putative transmembrane domain initially predicted as a signal peptide. Crucially, Yip7's neuroprotective function depends on its proper subcellular localization rather than the catalytic triad. Mechanistically, rather than eliminating Aβ, Yip7 binds intracellular Aβ42 to increase its neuronal retention, and this unexpectedly reduces Aβ42 toxicity to the organism. Finally, transcriptomics reveals that protection against Aβ42 toxicity by Yip7 is associated with selective suppression of Aβ‐upregulated genes including those codingribosomal proteins and molecular chaperones for protein folding. Together, these findings introduce a novel concept that intracellular sequestration of Aβ can be explored to mitigate its neurotoxicity.